FDA Approves Pembrolizumab/Chemo for Gastric and GEJ Adenocarcinoma

• The combination of pembrolizumab (Keytruda) and fluoropyrimidine- and platinum-containing chemotherapy offers a new option for the treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
• Findings from the phase 3 KEYNOTE-859 (NCT03675737) support this decision.
• Pembrolizumab is currently approved in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the treatment of locally advanced unresectable or metastatic HER2-positve gastric or GEJ adenocarcinoma.

The FDA has approved pembrolizumab and fluoropyrimidine- and platinum-containing chemotherapy for treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

Findings from the phase 3 KEYNOTE-859 (NCT03675737) support this regulatory decision as the combination demonstrated a significant improvement in overall survival (OS) vs chemotherapy alone. These results were independent of PD-L1 expression and in patients who were HER2-negative. The combination was previously approved for patients with HER2-positive gastric or GEJ adenocarcinoma.²

"[This approval] confirms the activity of immune checkpoint inhibitors and PD-1 inhibitors in combination with chemotherapy in HER2-negative recurrent/metastatic gastric cancer. Now, it really changes the treatment landscape of gastric cancer. This is a really good news for those patients for improved outcome without increasing toxicity," said Sun Young Rha, MD, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea, and principal investigator of KEYNOTE-859.

The randomized, double-blind study had an enrollment of approximately 1579 patients with HER2-negative, previously untreated, unresectable, or metastatic gastric or GEJ adenocarcinoma. Patients in the experimental arm received pembrolizumab200 mg every 3 weeks for up to approximately 2 years in combination with fluoropyrimidine- and platinum-containing chemotherapy.

The study’s primary end point was OS. The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), the percentage of patients who experienced adverse events (AEs), and the percentage of patients who discontinued the study drugs due to AEs.

At a median follow-up of 31.0 months (range, 15.3-46.3 months), the median OS was 12.9 months (95% CI, 11.9-14.0 months) with pembrolizumab plus chemotherapy vs 11.5 (95% CI, 10.6-12.1 months) with placebo plus chemotherapy (hazard ratio [HR] 0.78, 95% CI 0.70-0.87; P < .0001). The median PFS was 6.9 months (95% CI, 6.3-7.2 months) vs 5.6 months (95% CI, 5.5-5.7 months), respectively (HR 0.76, 95% CI, 0.67-0.85; P < .0001). The survival results were consistent in the subgroup populations.

Pembrolizumab plus chemotherapy led to an ORR of 51.3% (95% CI, 47.7%-54.8%) compared with 42.0% (95% CI, 38.5%-45.5%) in the placebo plus chemotherapy arm (P = .00009). The median DoRobserved with pembrolizumab plus chemotherapy was 8.0 months (range, 1.2-41.5+) compared with 5.7 months (range, 1.3-34.7+).

For safety, treatment-related adverse events (TRAEs) of any grade were seen in 95.7% of the pembrolizumab plus chemotherapy arm vs 93.5% of the placebo plus chemotherapy arm. TRAEs were grade 3-5 among 59.4% of the pembrolizumab arm vs 51.1% of the placebo arm, and TRAEs led to death in 1.0% vs 2.0%, respectively. Serious TRAEs occurred in 23.4% of pembrolizumab arm vs 18.6% of the placebo arm. Treatment discontinuations occurred in 26.4% of the pembrolizumab plus chemotherapy arm compared with 20.1% of the placebo plus chemotherapy arm. The most common TRAEs occurred in at least 15% of patients of the pembrolizumab/chemotherapy and placebo/chemotherapy groups combined. The most commonly occurring TRAEs included nausea (41.4% vs 41.4%), diarrhea (32.1% vs 27.2%, anemia (31.0% vs 26.9%), vomiting (27.4% vs 22.2%), and platelet count decrease (25.0% vs 22.5%).

Immune-mediated AEs of any-grade were observed in 27.1% of the pembrolizumab/chemotherapy arm vs 9.3% of the placebo/chemotherapy arm. Immune-mediated AEs were grade 3-5 in 7.9% of patients treated with pembrolizumab/chemotherapy vs 1.7% of those who received placebo/chemotherapy. Immune-mediated AEs led to death in fewer than 1% of patient in each arm. Hypothyroidism and hyperthyroidism were the 2 most common immune-mediated AEs having occurred in 15.3% vs 4.3% and 5.6% vs 1.7% of patients in the pembrolizumab plus chemotherapy vs placebo plus chemotherapy arm, respectively.³

The FDA accepted the supplemental biologics license application for the indication in April 2023.

Merck, pembrolizumab’s manufacturer, is still evaluating the drug in gastrointestinal cancers, including advanced HER2-positve gastric cancer and early-stage gastric cancer. Merck is also continuing to evaluate pembrolizumab in hepatic, biliary tract, esophageal, pancreatic, and colorectal cancers.²

REFERENCES:

1. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. News release. U.S. Food & Drug Administration. November 16, 2023. Accessed November 16, 2023. https://tinyurl.com/5fcr79ez

2. FDA accepts application for Merck's Keytruda (pembrolizumab) plus chemotherapy as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. News release. Merck. April 13, 2023. Accessed November 16, 2023. https://tinyurl.com/449533t6

3. Rha SY, Wyricz LS, Weber PEY, et al. Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. Ann Oncol. 2023;34(3):313-320. doi:10.1016/j.annonc.2023.01.006